(19) & (11) EP 1 353 699 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 47/48 (2006.01) A61K 31/585 (2006.01) 01.02.2012 Bulletin 2012/05 B82Y 5/00 (2011.01) A61P 15/18 (2006.01) A61P 15/12 (2006.01) (21) Application number: 01271230.3 (86) International application number: (22) Date of filing: 20.12.2001 PCT/IB2001/002604 (87) International publication number: WO 2002/049674 (27.06.2002 Gazette 2002/26) (54) Beta-cyclodextrin-drospirenone inclusion complexes Einschlusskomplexe von Drospirenone und Beta-Cyclodextrin Complexes d’inclusion béta-cyclodextrine-drospirenone (84) Designated Contracting States: • KRATTENMACHER ROLF: "Drospirenone: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Pharmacology and pharmacokinetics of a unique MC NL PT SE TR progestogen." CONTRACEPTION, vol. 62, no. 1, Designated Extension States: July 2000 (2000-07), pages 29-38, XP000993492 LT LV RO SI ISSN: 0010-7824 • NORMAN P ET AL: "Drospirenone: (30) Priority: 20.12.2000 EP 00610134 Contraceptive, hormone replacement therapy, 20.12.2000 US 256483 P aldosterone antagonist, progestogen: 1,2- dihydrospirorenone, SH-470, ZK-30595." DRUGS (43) Date of publication of application: OF THE FUTURE, vol. 25, no. 12, December 2000 22.10.2003 Bulletin 2003/43 (2000-12), pages 1247-1256, XP000993474 ISSN: 0377-8282 (73) Proprietor: Bayer Pharma Aktiengesellschaft • UEKAMA, K. ET AL: "Inclusion complexations of 13353 Berlin (DE) steroid hormoneswith cyclodextrins inwater and in solid phase" INT. J. PHARM., 1982, VOL. 10, (72) Inventors: NO. 1, PAGES 1-15, XP000610489 • BACKENSFELD, Thomas • KRALOVA, K. ET AL: "Interactions of beta 13127 Berlin (DE) -cyclodextrin with steroid compounds in • HEIL, Wolfgang aqueous solutions" PHARMAZIE, 1989, VOL. 44, 21435 Stelle (DE) NO. 9, PAGES 623-5, XP000611476 • HERMENS W.A.J.J.: "Delivery of hormones: (74) Representative: Plougmann & Vingtoft A/S Somenew concepts" PHARM. WEEKBL. SCI. ED., Sundkrogsgade 9 1992, VOL. 14, NO. 4 A, PAGE(S) 253-257, P.O. Box 831 XP002167344 NETHERLANDS 2100 Copenhagen Ø (DK) • K. UEKAMA: "CYCLODEXTRIN INCLUSION COMPOUNDS: EFFECTS ON STABILITY AND (56) References cited: BIO-PHARMACEUTICAL PROPERTIES" TOPICS EP-A- 0 398 460 WO-A-96/02277 IN PHARMACEUTICAL SCIENCES, EDS. D.D. WO-A1-01/15701 FR-A- 2 515 187 BREIMER AND P. SPEISER, 1987, ELSEVIER GB-A- 2 109 381 SCIENCE PUBLISHERS B.V. (BIOMEDICAL DIVISION), PAGES 181-194, XP002167345 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 353 699 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 353 699 B1 • UEKAMA K ET AL: "CYCLODEXTRIN DRUG • MELIA C D ET AL: "Review article: Mechanisms CARRIER SYSTEMS" CHEMICAL REVIEWS,US, of drug release from tablets and capsules. 2. AMERICAN CHEMICAL SOCIETY. EASTON, vol. Dissolution", ALIMENTARY PHARMACOLOGY 98, no. 5, 1 July 1998 (1998-07-01), pages AND THERAPEUTICS, vol. 3, no. 6, 1989, pages 2045-2076, XP000771829 ISSN: 0009-2665 513-525, ISSN: 0269-2813 • DALLA BELLA M ET AL: "CYCLODEXTRINS", DRUGS OF THE FUTURE, PROUS SCIENCE, ES, Remarks: vol. 8, no. 5, 1 January 1983 (1983-01-01) , pages Thefile contains technical information submitted after 391-394, XP008020709, ISSN: 0377-8282 the application was filed and not included in this specification 2 EP 1 353 699 B1 Description FIELD OF INVENTION 5 [0001] The present invention relates to an inclusion complex formed betweenβ -cyclodextrin and drospirenone and to methods of providing such an inclusion complex. Moreover, the present invention relates to the use of said inclusion complex in pharmaceutical compositions for use as a medicament in the treatment of symptoms associated with men- opause and in female contraception. 10 BACKGROUND OF THE INVENTION [0002] Drospirenone (6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21,17-carbolactone), which may be pre- pared substantially as described in e.g. US 4,129,564 or WO 98/06738, is only sparingly soluble in aqueous media at various pH values. 15 [0003] The water solubility of a compound is extremely pertinent with regards to its utility In industry, particularly in the pharmaceutical industry where there is a strong link between water solubility and bioavailability. The therapeutic efficiency of drospirenone may be improved by increasing its overall water solubility, thus providing for routes of admin- istration alternative to those proceeding via the gastrointestinal tract, where absorption is slow and then rapidly cleared from circulating blood by the liver. 20 [0004] Cyclodextrins are known to solubilize nonpolar compounds and improve the absorption of certain compounds by forming complexes with said compounds. The cyclodextrins are frequently derivatized in order to improve the solubility or to accommodate appropriately the compound of interest. However, certain compounds are not well accommodated by the cavity of the some of the cyclodextrin molecules. [0005] Drospirenone, in its uncomplexed form, is known from DE 26 52 761 in which its use as a diuretic compound 25 is disclosed. [0006] EP 0 398 460 described the use of drospirenone for contraception and for symptoms associated with meno- pause. [0007] U5 4,596,795 discloses a complex between α-, p- and γ-cyclodextrins and derivatives thereof with testosterone, progesterone, and estradiol and the solubility of said complexes. 30 [0008] US 5,885,978 relates to a composition comprising an adrenal cortical steroid and cyclodextrin prepared by clathrating the adrenal cortical steroid in the cyclodextrin using a homomixer. [0009] US 5,376,641 discloses a method of making a steroid water soluble by mixing a steroid and a branched beta cyclodextrin together in water for a period of 4 to 24 hours under ambient conditions. [0010] US 5,376,641 discloses a method for making a steroid water soluble by complexing the steroid with branched 35 β-cyclodextrin. [0011] US 4,727,064 discloses a method of improving the dissolution properties of.a steroid by forming a solid com- prising at least one of testosterone, progesterone and estradiol as an inclusion complex with a poly-β-cyclodextrin and /or hydroxypropyl-β-cyclodextrin adapted for administration by buccal route. [0012] FR 2 515 187 discloses inclusion complexes between γ-cyclodextrines and various steroids, such as a spironol- 40 actone steroid. [0013] WO 96/02277 discloses pharmaceutical compositions containing cyclodextrin-clathrate complexes of steroid sexual hormones for protection against oxidative degradation of steroids. SUMMARY OF THE INVENTION 45 [0014] The invention relates to an inclusion complex between β-cyclodextrin and 6β,7β; 15β,16β-dimethylene-3-oxo- 17α-pregn-4-ene-21,17-carbolactone (drospirenone) where the molar ratio between drospirenone and the β-cyclodextrin is 1:3. [0015] The invention also relates to a method for producing the inclusion complex according to the invention. 50 [0016] One object of the present invention is to increase the water-solubility of drospirenone. The present invention thus further discloses methods for improving the solubility of drospirenone, said method comprising forming an inclusion complex between drospirenone and β-cyclodextrin. [0017] In a further aspect of the invention, pharmaceutical compositions comprising an inclusion complex of dros- pirenone and β-cyclodextrin are described. Consequently, the inclusion complex between drospirenone andβ -cyclo- 55 dextrin for use for female contraception or for the treatment of menopausal symptoms are defined herein. 3 EP 1 353 699 B1 DETAILED DESCIPTION OF THE INVENTION [0018] The term "inclusion complex" is intended to mean a complex wherein at least a moiety of drospirenone has inserted itself, at least partially, into the cavity of cyclodextrin. 5 [0019] In efforts to improve the functional utility of drospirenone, research has led- to a new chemical entity, an inclusion complex between β- cyclodextrin and drospirenone in a motar ratio of 3:1. [0020] The β-cyclodextrin may be modified such that some or all of the primary or secondary hydroxyls of the macrocyle, or both, may be alkylated or acylated. Methods of modifying these alcohols are well known to the person skilled in the art and many derivatives are commercially available. The β-cyclodextrin may be modified such that one or more of the 10 primary or secondary hydroxyls of the macrocyle, or both, may be alkylated or acylated. Methods of modifying these alcohols are well known to the person skilled in the art and many are commercially available. Thus, some or all of the hydroxyls of β-cyclodextrin may have be substituted with an O-R group or an O-C(O)-R, wherein R is an optionally substitutedC 1-6 alkyl, an optionally substituted C 2-6alkenyl, anoptionally substituted C 2-6 alkynyl,an optionally substituted aryl or heteroaryl group. R may be methyl, ethyl, propyl, butyl, pentyl, or hexyl group. Consequently, O-C (O)-R may be 15 an acetate. Furthermore, R may be such as to derivatizeβ -cyclodextrin with the commonly employed 2-hydroxyethyl group, or 2-hydroxypropyl group. Moreover, the β-cyclodextrin alcohols may be perbenzylated, per-benzoylated, or benzylated or benzoylated on just one face of the macrocycle, or wherein only 1, 2, 3, 4, 5, or 6 hydroxyls are benzylated or benzoylated. The hydroxyl groups of β-cyclodextrin may be per-alkylated or per-acylated such as permethylated or per-acetylated, or alkylated or acylated, such as methylated or acetylated, on just one face of the macrocycle, or wherein 20 only 1, 2, 3, 4, 5, or 6 hydroxyls are alkylated or acylated, such as methylated or acetylated.